Taking a hint from natural antibiotics, a startup spun out of Stanford University is developing a way to chemically alter existing drugs to dramatically improve their half-life.
Researchers at Amplyx Pharmaceuticals decorate drug compounds with molecules designed to bind to specific proteins within cells, as well as binding to the drug’s treatment target. By sequestering the drugs within cells, the researchers hope to protect them from the body’s efforts to destroy them. So far, the company has developed long-lasting versions of a protease inhibitor to fight HIV, as well as the antibiotic carbapenem. Amplyx is now developing new versions of a number of drugs that fight infection, and aims to test them in clinical trials within the next two years.
An effective drug needs to have a relatively long half-life in the bloodstream so that it has time to get to its target before metabolizing enzymes in the liver break it down. Other researchers and biotechnology companies are attempting to deal with this problem by enveloping drugs in nanoparticles or other materials that slow their breakdown. Amplyx is instead altering the molecules themselves.
“We’re hoping this will be quite generally useful,” says Gerald Crabtree, a biologist at Stanford, in whose lab the research originated. “One of the things I like about this approach is the combinatorial nature of the synthesis of the molecules.” Researchers have developed a number of stabilizing structures–those that bind to intracellular proteins–as well as a number of “linkers,” which connect the stabilizers to the drug.
Amplyx’s technology emerged from the study of a handful of large-molecule drugs, such as the immunosuppressant rapamycin, that are derived from microbes. Large molecules often make poor drugs, in part because the body quickly metabolizes them–but despite this, drugs such as rapamycin actually last longer in the blood. Crabtree and his team discovered that rapamycin, originally derived from bacteria in the soil on Easter Island, and related compounds, works well because it attaches to a group of proteins within cells called FK506 binding proteins.
“We wondered if we could generalize this to a way of increasing stability for many drugs with problematic pharmacology, which can make them unusable or inconvenient to take,” says Crabtree. “Some drugs have to be taken five times per day, which in turn leads to patient compliance issues.”
To create longer-lasting drugs, the researchers generated chemical structures that mimic those found in rapamycin and are designed to bind to the FK506 binding proteins inside the cell. Researchers then attached the structures to the drug chemically. “Red blood cells have a lot of the binding proteins, so the drug binds tightly to them and slowly leaches out of blood cells,” says Jason Gestwicki, a biologist at the University of Michigan who is collaborating with Amplyx.